Abstract B004: Genomic loss of TP53 impairs AR-targeted activity in metastatic prostate cancer
Authors: Wanting Han, Michael D. Nyquist, Ilsa Coleman, Navonil De Sarkar, Lisa Ang, Eva Corey, Peter S. Nelson
Journal: Cancer Research (2023)

Abstract Background: Metastatic prostate cancer (mPC) is notable for a spectrum of recurrent genomic alterations, some associated with overall prognosis and others predicting response to specific therapeutics. Standard mPC interventions are designed to suppress the signaling program regulated by the androgen receptor (AR). These include androgen deprivation therapy (ADT) to reduce AR ligand levels and AR signaling inhibitors (ARSI) that directly impair AR function. While ADT and ARSI produce clinical responses in most patients, the duration and depth of response vary greatly. In addition, specific recurring genomic alterations are associated with shorter responses after ADT and ARSI therapy. Among these are mutations and/or genomic copy loss involving key tumor suppressor genes, including PTEN, RB1 and TP53. However, the mechanistic contribution of TP53 loss to AR signaling and resistance to AR pathway-directed therapy remains unresolved. Methods: Isogenic prostate cancer cell lines with intact and TP53 deletions were constructed using CRISPR/Cas9. The transcriptome profiles were determined by RNA-seq, and ChIP-seq was used to determine the chromatin landscapes of AR localization. In addition, we performed ATAC-seq to assess chromatin accessibility. Finally, to further validate the findings, we comprehensively analyzed AR-regulated gene expression and AR cistromes across a panel of patient-derived xenograft (PDX) models and clinical cohorts of mPC patient samples with respect to TP53 status. Results: Compared to TP53-wild-type (WT) cells, the transcriptional results of isogenic knockout TP53 lines showed impaired AR canonical activity. However, the downregulated AR response pathway is not caused by reduced levels of AR transcript or protein levels. Additionally, a similar trend was also found while comparing TP53-WT PDX models with TP53-loss models. We found that the loss of TP53 can shift the chromatin binding of AR, and the altered AR binding sites correlated with genes involved in neurogenesis pathways, which provide a potential mechanism of how the loss of TP53 might impact AR signaling and promote ADT and ARSI treatment resistance. We also identified additional AR chromatin binding sites that were enriched due to the loss of TP53. The targets potentially regulated by these sites are involved in multiple pathways, including cell morphogenesis involved in differentiation and response to the endogenous stimulus. Conclusions and Future Directions: Overall, the results indicate that in addition to altering DNA damage and repair pathways and contributing to cancer progression, genetic loss of TP53 in mPC may directly impair ADT and ARSI therapies, partially through alteration of AR chromatin activity. In addition, the AR cistrome reprogramming resulting from TP53 loss could also affect other pathways that could be exploited to overcome ARSI treatment resistance. Citation Format: Wanting Han, Michael D. Nyquist, Ilsa Coleman, Navonil De Sarkar, Lisa Ang, Eva Corey, Peter S. Nelson. Genomic loss of TP53 impairs AR-targeted activity in metastatic prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B004.